Efficacy of Hypertonic Dextrose Proliferation Therapy for the Treatment of Rotator Cuff Lesions: A Meta-Analysis.

Background: One of the most prevalent disorders of the shoulder is rotator cuff tendinosis, which is a major contributor to shoulder discomfort and shoulder joint dysfunction. Rotator cuff tendinosis occurs in 0.3% to 5.5% of people worldwide and is diagnosed in 0.5% to 7.4% of people in China annually. We performed a meta-analysis to assess whether hypertonic dextrose proliferation therapy, a form of prolotherapy, improves the well-being of patients with rotator cuff injuries. Methods: We screened the literature by searching the PubMed, Embase, Cochrane Library, and Web of Science databases for the search terms prolotherapy, hypertonic dextrose, and rotator cuff. We identified and evaluated studies that treated individuals with rotator cuff lesions with hypertonic dextrose proliferation therapy (intervention) or a placebo (control). The outcome measures for patients with rotator cuff lesions were the visual analog scale score, the shoulder pain and disability index, and other metrics. These metrics were used to evaluate the effects of hypertonic dextrose proliferation therapy on individuals with rotator cuff diseases by meta-analysis. Results: The meta-analysis used data from 6 studies. In the 6 studies, the visual analog scale scores improved in the intervention and control categories, with greater improvement for the intervention category compared with the control category (standardized mean difference [SMD], 1.10 [95% CI, 0.37-1.83]; P = .04). In the studies that measured other outcomes, greater improvement for the intervention category compared with the control category was seen for the shoulder pain and disability index score (SMD, 8.13 [95% CI, 5.34-10.91]; P < .01), flexion (SMD, 5.73 [95% CI, 0.99-10.47]; P < .01), and abduction (SMD, 6.49 [95% CI, 0.66-12.31]; P < .05). There were no statistically significant differences of internal rotation between the intervention and control categories (SMD, -1.74 [95% CI, -4.25 to 0.78]; P = .18) and external rotation (SMD, 2.78 [95% CI, -0.13 to 5.69]; P = .06). Conclusion: The findings of this study suggest that individuals with rotator cuff injuries may benefit from hypertonic dextrose proliferation therapy based on the visual analog scale score, the shoulder pain and disability index score, flexion, and abduction. These results must, nevertheless, be supported by high-caliber follow-up research.

Electroacupuncture Improves Learning and Memory Abilities via Activating AMPK/mTOR-Induced Autophagy in APP/PS1 Mice.

Alzheimer's disease (AD) has become a global public health problem characterized by memory and cognitive impairments. Electroacupuncture (EA) has been indicated to exert promising therapeutic effects on AD. This study aimed to further investigate the underlying mechanism of EA in AD treatment. APP/PS1 transgenic mice and wide-type mice underwent with or without EA treatment at GV20 and BL23 acupoints. Morris water maze test was utilized for examining the learning and memory of mice. Hematoxylin-eosin, Congo red, immunofluorescence, and TUNEL staining were employed for detecting the pathological changes of mouse brain hippocampus. Western blotting was implemented for measuring protein levels of autophagy- and AMPK/mTOR pathway-associated markers. APP/PS1 mice exhibited significant impairments in the spatial learning and memory. EA treatment improved the cognitive impairments, reduced amyloid-beta (Aß) deposition, and alleviated neuronal apoptosis in the hippocampal tissues of APP/PS1 mice. EA promoted autophagy and activated the AMPK/mTOR signaling pathway in the hippocampus of APP/PS1 mice. EA improves the cognitive deficits, enhances Aß clearance, and attenuates neuronal apoptosis in APP/PS1 mice in part by activating AMPK/mTOR-mediated autophagy.

[New advances in the diagnosis and treatment of biliary atresia]. / 胆道闭锁的诊断及治疗新进展.

The diagnosis of biliary atresia (BA) is mainly based on clinical manifestations, screening, and related biochemistry tests. In recent years, the development of blood biomarkers and the improvement in ultrasound examination have made it possible for BA to be diagnosed at a younger age. In particular, matrix metalloproteinase-7 shows high sensitivity and specificity and has a higher diagnostic efficiency than existing biochemical parameters, thereby holding a promise for clinical application. Sound touch elastography can increase the diagnostic efficiency for BA in terms of diagnosis and prognostic evaluation. Surgery is still the only method for the treatment of BA at present, with the preferred surgical treatment regimen of Kasai portoenterostomy combined with pharmacotherapies for alleviating infection and inflammation, and the patients who fail Kasai portoenterostomy or have liver dysfunction may require liver transplantation to save their lives. Therefore, the current research on BA should focus on the biomarkers for early diagnosis, specifically targeted drugs, and drugs for preventing progressive liver fibrosis. This article reviews the current diagnosis and treatment methods for BA and discusses the potential research directions.

Severe autoimmune-mediated thrombocytopenia in an elderly woman.

The efficacy of immunotherapies that use antibodies to block programmed cell death 1 (PD-1) has been extensively investigated for lung cancer. Along with reactivation of the patient's immune response to tumour cells, immune-related adverse effects with anti-PD1 therapy have been reported. We report an 80-year-old woman who had suffered from a primary lung adenocarcinoma pre-treated with pembrolizumab and was admitted to our hospital with serious autoimmune-mediated thrombocytopenia induced by pembrolizumab.

Serum Metabolomics Study of Nonsmoking Female Patients with Non-Small Cell Lung Cancer Using Gas Chromatography-Mass Spectrometry.

The incidence of nonsmoking female patients with non-small cell lung cancer (NSCLC) has increased in recent decades; however, the pathogenesis of patients is unclear, and early diagnosis biomarkers are in urgent need. In this study, 136 nonsmoking female subjects (65 patients with NSCLC, 6 patients with benign lung tumors, and 65 healthy controls) were enrolled, and their metabolic profiling was investigated by using pseudotargeted gas chromatography-mass spectrometry. A total of 56 annotated metabolites were found and verified to be significantly different in nonsmoking females with NSCLC compared with the control. The metabolic profiling was featured by disturbed energy metabolism, amino acid metabolism, oxidative stress, lipid metabolism, and so on. Cysteine, serine, and 1-monooleoylglycerol were defined as the biomarker panel for the diagnosis of NSCLC patients. 98.5 and 91.4% of subjects were correctly distinguished in the discovery and validation sets, respectively. The biomarker panel was also useful for the diagnosis of in situ malignancy patients, with an accuracy of 97.7 and 97.8% in the discovery and validation sets, respectively. The study provides a biomarker panel for the auxiliary diagnosis of nonsmoking females with NSCLC.

Colorectal cancer progression is associated with accumulation of Th17 lymphocytes in tumor tissues and increased serum levels of interleukin-6.

Colorectal cancer is a significant worldwide health problem, and an altered immunoresponse plays an important role in colorectal tumorigenesis and cancer progression. T helper 17 (Th17) lymphocytes (a subgroup of CD4(+) T cells), together with the related cytokines, such as interleukin (IL)-6 and IL-17A, participate in cancer-related immunity. In this study, we measured the percentage of Th17 cells in peripheral blood mononuclear cells (PBMCs) and the levels of IL-17A and IL-6 in serum samples or tumor tissues, prepared from 40 colorectal cancer patients (a median age of 75 years), 32 age-matched healthy controls (a median age of 74 years), and 30 young healthy controls (a median age of 26 years). The percentage of Th17 cells in PBMCs and the serum IL-6 levels were higher in cancer patients than those in elderly controls, and they were associated with tumor progression. Moreover, the percentage of Th17 cells and the serum IL-6 levels were higher in elderly healthy controls than those in young healthy controls. In contrast, serum IL-17A levels were similar in the cancer patients and the elderly controls, although its serum levels were higher than those in young controls. Importantly, Th17 cells were accumulated in the intratumor and peritumor regions. In conclusion, the percentage of Th17 cells and the serum IL-6 level are significantly increased with aging, and their higher levels are correlated with colorectal cancer progression. The percentage of Th17 cells in PBMCs and the serum IL-6 level are potential biomarkers for predicting disease progression.

[Metabolic activity measured by ¹8F-FDG PET/CT in newly diagnosed patients with non-Hodgkin lymphoma: correlation with immunophenotype].

OBJECTIVE: To compare the metabolic activity by ¹8F-fluorodeoxyglucose (¹8F-FDG) uptake across the various histologic subtypes of non-Hodgkin lymphoma (NHL) and to investigate the relationship between metabolic activity and immunophenotype. METHODS: Positron emission tomography/computed tomography (PET/CT) studies of patients with newly diagnosed NHL from Jul 2010 to Mar 2012 were retrospectively reviewed, 82 patients were enrolled in our study according to the inclusion and exclusion criteria. The maximum standardized uptake value (SUVmax) of each patient reflecting the metabolic activity was recorded. Mean SUVmax of aggressive B-cell NHL, indolent B-cell NHL and T-cell NHL were compared. Pearson and Spearman test were used to analyze the relationship between SUVmax and immunophenotype. RESULTS: The SUVmax of various subtypes of lymphoma revealed a wide range from 0.9 to 40.3, but lesions of 79 patients in this study showed obviously FDG uptake. SUVmax of indolent B-cell NHL (4.5 ± 2.4) was significantly lower than that of aggressive B-cell NHL (13.1 ± 7.6) (P = 0.000), T-cell NHL (8.0 ± 3.8) (P = 0.03). SUVmax of aggressive B-cell NHL was significantly higher than that of indolent B-cell NHL, T-cell NHL (P = 0.000, P = 0.005). SUVmax of B-cell NHL had positive correlation with Ki-67 expression (r = 0.493, P = 0.001) and negative correlation with CD138 (r = -0.654, P = 0.008). While SUVmax of T-cell NHL had no correlation with Ki-67 expression (P = 0.213), but had negative correlation with CD56 (r = -0.545, P = 0.044). CONCLUSIONS: Different subtype of NHL manifests markedly different intensity of FDG uptake, but most lesions of lymphoma are FDG avid. Metabolic activity is lower in indolent B-cell NHL than in aggressive B-cell NHL and T-cell lymphoma, which is concordant with its aggressiveness. SUVmax of B-cell NHL correlates with expression of Ki-67 and CD138. SUVmax of T-cell NHL is associated with the expression of CD56, no correlation is detected between SUVmax of T-cell NHL and Ki-67 proliferation.

Efficacy of hypertonic dextrose proliferation therapy in the treatment of rotator cuff lesions: a meta-analysis.

BACKGROUND: One of the most prevalent illnesses of the shoulder is rotator cuff tendinosis, which is also a major contributor to shoulder discomfort and shoulder joint dysfunction. According to statistics, rotator cuff tendinosis occurs in 0.3-5.5% of cases and affects 0.5-7.4% of people annually. It will be necessary to conduct a meta-analysis to evaluate the efficacy of hypertonic glucose proliferation therapy in the treatment of rotator cuff problems. METHODS: The databases Cochrane PubMed, Library, Web of Science and EMbase, are retrieved by the computer. Individuals with rotator cuff lesions in the intervention group were treated with hypertonic dextrose proliferation therapy, whereas individuals in the control condition were treated with a placebo. Outcome markers for rotator cuff lesions patients; Pursuant to studies, the visual analogue scale (VAS) score, the shoulder pain & disability index (SPADI), & other metrics are used to evaluate the effects of hypertonic dextrose proliferation treatment on individuals with rotator cuff diseases. After carefully evaluating the calibre of the literature, data analysis was performed utilising the RevMan 5.3 programme. RESULTS: Meta-analysis finally contained 6 papers. In six investigations, the test & control group's VAS scores improved, with the test team's score considerably outperforming the control team [standardized mean difference (SMD): 1.10; 95% Cl: 0.37,1.83; P < 0.01], shoulder pain and disability index (SPADI) score (SMD:8.13; 95% Cl: 5.34,10.91; P < 0.01), Flexion (SMD:5.73; 95% Cl: 0.99,10.47; P < 0.05), Abduction (SMD:6.49; 95% Cl: 0.66,12.31; P < 0.05), Internal rotation (SMD:-1.74; 95% Cl: -4.25,0.78; P = 0.176) and External rotation (SMD:2.78; 95% Cl: -0.13,5.69; P = 0.062). CONCLUSION: The findings of this study suggest that individuals with rotator cuff injuries may benefit from hypertonic dextrose proliferation treatment based on the visual analogue scale (VAS) score, the Shoulder Pain and Disability Index (SPADI) score, Flexion, & Abduction. These results must, nevertheless, be supported by high-caliber follow-up research.

Prognostic evaluation of a multi-target magnetic bead-enriched circulating tumor cell-enriched identification system for colorectal cancer.

Background: Colorectal cancer (CRC) is the third most prevalent cancer in the world. Traditional tissue biopsy cannot provide dynamic monitoring of patients' tumors or reflect the characteristics of tumors in real time because the sampling process is invasive and accompanied by risks. Circulating tumor cells (CTCs) are considered a major cause of tumor metastasis, and investigating CTCs helps to understand the biology and vulnerability of malignant tumors during hematogenous metastasis. Methods: We sequentially used epithelial cell adhesion molecule (EpCAM)-coated immunoliposomal magnetic beads (Ep-IMBs) and vimentin-coated immunoliposomal magnetic beads (Vi-IMBs) to capture and characterize CTCs from 110 CRC patients. We further constructed a Cox risk regression model, optimized the model composition using backward stepwise regression, and finally applied nomograms to show the effect of each variable on survival risk. Results: The specificity of the CTCs enrichment and identification system was 100% and the sensitivity was 79.0%. Multivariate analysis indicated total CTC number was an important predictor for bad survival, whereas American Joint Committee on Cancer (AJCC) stage, lymph node metastasis, and carcinoembryonic antigen (CEA) level were associated with prognosis, and the risk of mortality was associated with the AJCC stage of the CRC. Conclusions: The CTC enrichment and identification system constructed in this research demonstrated superior accuracy. In addition, CTCs can be used as an important predictor for prognosis of patients with CRC, and the combination of other clinical predictive factors can help clinicians to better design individualized treatment regimens, which is of great clinical application value.

Undescribed steroidal alkaloids from the bulbs of Fritillaria ussuriensis Maxim and their anti-inflammatory activities.

In total, 16 undescribed steroidal alkaloids (1-16), along with nine known ones (17-25), were isolated from the bulbs of Fritillaria ussuriensis Maxim. Among the undescribed compounds mentioned, compounds 1-6, 8 bearing an 16ß-hydroxy substituent, as well as compounds 13 and 14 exhibited an unusual seven-membered skeleton. Their structures were established based on extensive spectroscopic analyses, including HRESIMS and NMR (1D and 2D), and comparison with the data reported in the literature. Furthermore, all the compounds were evaluated for their anti-inflammatory effect on the NO production of LPS-stimulated RAW264.7 cells. Compounds 1, 4, 11, 15, 22 and 24 could significantly inhibit NO production with IC50 values below 10 µM.

Effects of Viscum coloratum (Kom.) Nakai on collagen-induced rheumatoid arthritis.

ETHNOPHARMACOLOGICAL RELEVANCE: Viscum coloratum (Kom.) Nakai has been traditionally used in China for nearly a thousand years to treat rheumatic diseases. However, its efficacy and mechanisms in treating rheumatoid arthritis (RA) have not been demonstrated. AIM OF THE STUDY: To investigate the anti-arthritic effects and molecular mechanisms of Viscum coloratum (Kom.) Nakai on collagen-induced arthritic mice through network pharmacology technology and experimental validation. MATERIALS AND METHODS: First, the main ingredients of the extract of Viscum coloratum (Kom.) Nakai (EVC) were identified through chemical composition characterization using Ultra Performance Liquid Chromatography Tandem Mass Spectrometry (UPLC-MS). Then, the collagen-induced arthritis (CIA) model was established in DBA/1 J mice and the ameliorative effects of EVC on the progression of CIA mice were evaluated by oral treatment with different doses of the EVC for 28 days. After that, cytokine antibody microarray assay was used to detect the levels of multiple inflammation-related cytokines and chemokines in each group, and performed Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genome (KEGG) enrichment analysis. Subsequently, the potential target for the effective chemical components of EVC in treating RA was identified using various databases. Additionally, a drug-disease target protein-protein interaction network (PPI) was conducted using Cytoscape for visualization and clustering, while GO and KEGG enrichment analyses were performed with the Metascape database. Finally, identified phenotypes and targets by network pharmacology analysis were experimentally validated in vivo. RESULTS: Treatment with EVC significantly suppressed the severity of CIA with a dramatic reduction of paw swelling, arthritis index, levels of IgGs (IgG, IgG1, IgG2a, and IgG2b), multi-inflammation-related cytokines and chemokines on the progression of CIA. Histopathological examinations showed EVC could markedly inhibit inflammatory cell infiltration, tartrate-resistant acid phosphatase (TRAP) activity of osteoclast, and bone destruction. Furthermore, GO and KEGG enrichment analyses revealed that EVC could ameliorate RA by inhibiting osteoclast differentiation and regulating multiple signaling pathways including Osteoclast differentiation, IL-17, and TNF. PPI network analysis demonstrated that AKT1, MMP9, MAPK3, and other genes were highly related to EVC in treating RA. Finally, we proved that EVC could inhibit the expression of NFTAc1, MMP9, Cathepsin K, and AKT which were closely related to osteoclast activity. CONCLUSIONS: EVC could treat RA through multiple components, multiple targets, and multiple pathways. The present study demonstrated the therapeutic efficacy of EVC and its molecular mechanisms in treating RA, indicating that it would be a potent candidate as a novel botanical drug for further investigation.

Specific Kv1.3 blockade modulates key cholesterol-metabolism-associated molecules in human macrophages exposed to ox-LDL.

Cholesterol-metabolism-associated molecules, including scavenger receptor class A (SR-A), lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), CD36, ACAT1, ABCA1, ABCG1, and scavenger receptor class B type I, can modulate cholesterol metabolism in the transformation from macrophages to foam cells. Voltage-gated potassium channel Kv1.3 has increasingly been demonstrated to play an important role in the modulation of macrophage function. Here, we investigate the role of Kv1.3 in modulating cholesterol-metabolism-associated molecules in human acute monocytic leukemia cell-derived macrophages (THP-1 macrophages) and human monocyte-derived macrophages exposed to oxidized LDL (ox-LDL). Human Kv1.3 and Kv1.5 channels (hKv1.3 and hKv1.5) are expressed in macrophages and form a heteromultimeric channel. The hKv1.3-E314 antibody that we had generated as a specific hKv1.3 blocker inhibited outward delayed rectifier potassium currents, whereas the hKv1.5-E313 antibody that we had generated as a specific hKv1.5 blocker failed. Accordingly, the hKv1.3-E314 antibody reduced percentage of cholesterol ester and enhanced apoA-I-mediated cholesterol efflux in THP-1 macrophages and human monocyte-derived macrophages exposed to ox-LDL. The hKv1.3-E314 antibody downregulated SR-A, LOX-1, and ACAT1 expression and upregulated ABCA1 expression in THP-1 macrophages and human monocyte-derived macrophages. Our results reveal that specific Kv1.3 blockade represents a novel strategy modulating cholesterol metabolism in macrophages, which benefits the treatment of atherosclerotic lesions.

Effects of nicorandil in neuroprotective activation of PI3K/AKT pathways in a cellular model of Alzheimer's disease.

Nicorandil, an ATP-sensitive potassium (KATP) channel opener, is known to have protective effects on ischemic injury in heart and brain. One of the most important protective mechanisms is the anti-apoptotic effect on cardiomyocytes and neurons. This study explored the anti-apoptotic effect of nicorandil against neurotoxicity in SH-SY5Y cells overexpressing the Swedish mutant APP (APPsw) and the possible mechanisms involved. We used SH-SY5Y cells transiently transfected with APPsw as a cellular model of Alzheimer's disease. Cells were treated with nicorandil (0.1, 0.5, 1 mM) for 24 h with and without glibenclamide (10 µM), a KATP channel inhibitor. The cells were then collected for MTT, apoptosis assay, and Western blot. In addition, we also investigated the potential involvement of the PI3K/Akt pathway in nicorandil-mediated neuroprotection of APPsw cells. Our results showed that nicorandil dose-dependently increased cell viability and reduced the rate of apoptosis as measured by MTT assay and annexin V/PI staining. Western blot showed that nicorandil could upregulate Bcl-2 levels and downregulate Bax and caspase-3 expression. Further studies showed that nicorandil increased the levels of phospho-Akt and upregulated element-binding protein activity by PI3K activation. Applying a PI3K inhibitor, LY294002 blocked the protection. All these findings suggest that nicorandil might be a potential treatment option for Alzheimer's disease.

Glycometabolic Reprogramming of Microglia in Neurodegenerative Diseases: Insights from Neuroinflammation.

Neurodegenerative diseases (ND) are conditions defined by progressive deterioration of the structure and function of the nervous system. Some major examples include Alzheimer's disease (AD), Parkinson's disease (PD), and Amyotrophic lateral sclerosis (ALS). These diseases lead to various dysfunctions, like impaired cognition, memory, and movement. Chronic neuroinflammation may underlie numerous neurodegenerative disorders. Microglia, an important immunocell in the brain, plays a vital role in defending against neuroinflammation. When exposed to different stimuli, microglia are activated and assume different phenotypes, participating in immune regulation of the nervous system and maintaining tissue homeostasis. The immunological activity of activated microglia is affected by glucose metabolic alterations. However, in the context of chronic neuroinflammation, specific alterations of microglial glucose metabolism and their mechanisms of action remain unclear. Thus, in this paper, we review the glycometabolic reprogramming of microglia in ND. The key molecular targets and main metabolic pathways are the focus of this research. Additionally, this study explores the mechanisms underlying microglial glucose metabolism reprogramming in ND and offers an analysis of the most recent therapeutic advancements. The ultimate aim is to provide insights into the development of potential treatments for ND.

Serum exosomal coronin 1A and dynamin 2 as neural tube defect biomarkers.

No highly specific and sensitive biomarkers have been identified for early diagnosis of neural tube defects (NTDs). In this study, we used proteomics to identify novel proteins specific for NTDs. Our findings revealed three proteins showing differential expression during fetal development. In a rat model of NTDs, we used western blotting to quantify proteins in maternal serum exosomes on gestational days E18, E16, E14, and E12, in serum on E18 and E12, in neural tubes on E18 and E12, and in fetal neural exosomes on E18. The expression of coronin 1A and dynamin 2 was exosome-specific and associated with spina bifida aperta embryogenesis. Furthermore, coronin 1A and dynamin 2 were significantly downregulated in maternal serum exosomes (E12-E18), neural tubes, and fetal neural exosomes. Although downregulation was also observed in serum, the difference was not significant. Differentially expressed proteins were further analyzed in the serum exosomes of pregnant women during gestational weeks 12-40 using enzyme-linked immunosorbent assays. The findings revealed that coronin 1A and dynamin 2 showed potential diagnostic efficacy during gestational weeks 12-40, particularly during early gestation (12-18 weeks). Therefore, these two targets are used as candidate NTD screening and diagnostic biomarkers during early gestation. KEY MESSAGES: We used proteomics to identify novel proteins specific for NTDs. CORO1A and DNM2 showed exosome-specific expression and were associated with SBA. CORO1A and DNM2 were downregulated in maternal serum exosomes and FNEs. CORO1A and DNM2 showed good diagnostic efficacy for NTDs during early gestation. These two targets may have applications as NTD screening and diagnostic biomarkers.

Neutrophil extracellular traps accelerate vascular smooth muscle cell proliferation via Akt/CDKN1b/TK1 accompanying with the occurrence of hypertension.

OBJECTIVE: Neutrophil extracellular traps (NETs) can trigger pathological changes in vascular cells or vessel wall components, which are vascular pathological changes of hypertension. Therefore, we hypothesized that NETs would be associated with the occurrence of hypertension. METHODS: To evaluate the relationship between NETs and hypertension, we evaluated both the NETs formation in spontaneously hypertensive rats (SHRs) and the blood pressure of mice injected phorbol-12-myristate-13-acetate (PMA) via the tail vein to induce NETs formation in arterial wall. Meanwhile, proliferation and cell cycle of vascular smooth muscle cells (VSMCs), which were co-cultured with NETs were assessed. In addition, the role of exosomes from VSMCs co-cultured with NETs on proliferation signaling delivery was assessed. RESULTS: Formation of NETs increased in the arteries of SHR. PMA resulted in up-regulation expression of citrullinated Histone H3 (cit Histone H3, a NETs marker) in the arteries of mice accompanied with increasing of blood pressure. NET treatment significantly increased VSMCs count and accelerated G1/S transition in vitro . Cyclin-dependent kinase inhibitor 1b (CDKN1b) was down-regulated and Thymidine kinase 1 (TK1) was up-regulated in VSMCs. Exosomes from VSMCs co-cultured with NETs significantly accelerated the proliferation of VSMCs. TK1 was up-regulated in the exosomes from VSMCs co-cultured with NETs and in both the arterial wall and serum of mice with PMA. CONCLUSION: NETs promote VSMCs proliferation via Akt/CDKN1b/TK1 and is related to hypertension development. Exosomes from VSMCs co-cultured with NETs participate in transferring the proliferation signal. These results support the role of NETs in the development of hypertension.

Neural Stem Cell-Derived Exosomal Netrin1 Contributes to Neuron Differentiation of Mesenchymal Stem Cells in Therapy of Spinal Bifida Aperta.

Spinal bifida aperta (SBA) is a congenital malformation with a high incidence. Bone marrow mesenchymal stem cell (BMSC) transplantation has the potential to repair the structure of damaged tissues and restore their functions. This is an optional treatment that can be used as a supplement to surgery in the treatment of SBA. However, the application of BMSCs is limited, as the neuronal differentiation rate of BMSCs is not satisfactory when used in treating severe SBA. Thus, we aimed to assess the effect of neural stem cell (NSC)-derived exosomes on BMSC neuronal differentiation and observe the therapeutic effect in an ex vivo rat SBA embryo model. We found that NSC-derived exosomes increased the neuronal differentiation rate of BMSCs in vitro and in the SBA embryo model ex vivo. Proteomic analysis showed that NSC-derived exosomes were enriched in Netrin1, which positively regulated neuronal differentiation. Netrin1 increased the neuronal differentiation rate of BMSCs and NSCs and upregulated the expression of the neuronal markers, microtubule-associated protein (Map2), neurofilament, and ß3-tubulin. Bioinformatic analysis revealed that Netrin1 treatment increased the expression of the transcription factors Hand2 and Phox2b, related to neuronal differentiation. Furthermore, the Netrin1-induced NSC neuronal differentiation was significantly blocked by Phox2b knockdown. We suggest that NSC-derived exosomal Netrin1 induces neuronal differentiation via the Hand2/Phox2b axis by upregulating the expression of Hand2 and Phox2b. Therefore, NSC-derived exosomes are a critical inducer of BMSC neuronal differentiation and represent a potential treatment agent that can benefit BMSC treatment in SBA.

Protective role of the alpha-1-antitrypsin in intervertebral disc degeneration.

BACKGROUND: Intervertebral disc degeneration is a complex disease with high prevalence. It suggests that cell death, senescence, and extracellular matrix degradation are involved in the pathogenesis. Alpha-1 antitrypsin (AAT), a serine protease inhibitor, was previously correlated with inflammation-related diseases. However, its function on intervertebral disc degeneration remains unclear. METHODS: A latex-enhanced immunoturbidimetric assay measured the serum level of AAT. Real-time polymerase chain reaction (RT-qPCR) and western blot were used to testify the expression of RNA and proteins related to cell apoptosis and the Wnt/ß-catenin pathway. The animal model for intervertebral disc degeneration was built by disc puncture. The degeneration grades were analyzed by safranin o staining. RESULTS: We showed that alpha-1 antitrypsin could ameliorate intervertebral disc degeneration in vitro and in vivo. We also found that the serum alpha-1 antitrypsin level in Intervertebral disc degeneration patients is negative related to the severity of intervertebral disc degeneration. Moreover, alpha-1 antitrypsin was also showed to suppress tumor necrosis factor-alpha (TNF-α) induced WNT/ß-catenin signaling pathway activation in human nucleus pulposus cells. CONCLUSIONS: Our study provides evidence for AAT to serve as a potential therapeutic reagent for the treatment of intervertebral disc degeneration.

PIWI-interacting RNA sequencing profiles in maternal plasma-derived exosomes reveal novel non-invasive prenatal biomarkers for the early diagnosis of nonsyndromic cleft lip and palate.

BACKGROUND: Congenital malformations are common birth defects with high neonatal morbidity and mortality. It is essential to find simpler and more efficient biomarkers for early prenatal diagnosis. Therefore, we investigated PIWI-interacting RNAs (piRNAs) as potential prenatal biomarkers in plasma-derived exosomes from pregnant women carrying foetuses with congenital malformations. METHODS: Small RNA sequencing was used to screen piRNA biomarkers in plasma-derived exosomes of five pregnant women carrying foetuses with nonsyndromic cleft lip and palate (nsCLP) and five women carrying normal foetuses. Differentially expressed piRNAs were verified in 270 pregnant women, including 111 paired women carrying foetuses with congenital malformations and normal foetuses (at 24 gestational weeks), 10 paired women carrying foetuses with nsCLP and normal foetuses (at 15-19 gestational weeks), and 28 women at different stages of normal pregnancy. piRNA biomarkers were also verified in placentas, umbilical cords, fetal medial calf muscles, and lip tissues of nsCLP and normal foetuses. FINDINGS: We identified a biomarker panel of three pregnancy-associated exosomal piRNAs (hsa-piR-009228, hsa-piR-016659, and hsa-piR-020496) could distinguish nsCLP foetuses from normal foetuses. These three piRNAs had better diagnostic accuracy for nsCLP at the early gestational stage, at which time typical malformations were not detected upon prenatal ultrasound screening, and had diagnostic value for neural tube defects (NTDs) and congenital heart defects (CHDs). INTERPRETATION: Our work revealed the potential clinical applications of piRNAs for predicting nsCLP, NTDs, and CHDs. FUNDING: National Key Research and Development Program, National Natural Science Foundation of China, and LiaoNing Revitalization Talents Program .

Efficacy of acupuncture for sciatica: study protocol for a randomized controlled pilot trial.

BACKGROUND: Acupuncture is widely used for pain diseases while evidence of its efficacy for sciatica is insufficient. We aim to explore the feasibility and efficacy of acupuncture with different acupoint selecting strategies for sciatica induced by lumbar disc herniation. METHODS: This is a multicenter, three-arm, patient-assessor-blinded randomized controlled pilot trial. Ninety patients will be assigned randomly into 3 groups including disease-affected meridians (DAM) group, non-affected meridians (NAM) group, and sham acupuncture (SA) group in a 1:1:1 ratio. The trial involves a 4-week treatment along with follow-up for 22 weeks. The primary outcome is the change of leg pain intensity measured by the visual analogue scale (VAS) from baseline to week 4 after randomization. Secondary outcomes include functional status, back pain intensity, and quality of life. Adverse events will also be recorded. DISCUSSION: The results will inspire the optimal acupuncture strategy for sciatica and help establish a better design as well as power calculation for a full-scale study. TRIAL REGISTRATION: ChiCTR2000030680 (Chinese Clinical Trial Registry, http://www.chictr.org.cn , registered on 9 March 2020).